DETERMINATION OF ALPHA-1-ADRENOCEPTOR SUBTYPE SELECTIVITY BY [H-3] PRAZOSIN DISPLACEMENT STUDIES IN GUINEA-PIG CEREBRAL-CORTEX AND RAT SPLEEN MEMBRANES

1 [H-3]-prazosin homogeneously labels alpha-1-adrenoceptors in guinea-pig cerebral cortex and rat spleen membranes with dissociation constants of 1.28 and 1.49 x 10(-10) M respectively. 2 Phentolamine and WB 4101 displacement studies show that guinea-pig cerebral cortex contains 30% alpha-1A- and 70% alpha-1B-adrenoceptor subtypes, whereas rat spleen contains a virtually homogeneous alpha-1B-adrenoceptor subtype population. The alpha-1A-adrenoceptor population of rat thoracic aorta is predominantly of the alpha-1A-adrenoceptor subtype, and in guinea-pig thoracic aorta it is mainly of the alpha-1B-adrenoceptor subtype. 3 Half of the compounds displacing [H-3]-prazosin bound to guinea-pig cerebral cortex membranes display alpha-1A-adrenoceptor selectivity. Among these compounds, WB 4101 and methoxamine are most selective, displaying selectivity ratios of approximately 38 and approximately 26 respectively. 4 The affinity constants of the non-selective compounds for the alpha-1-adrenoceptors in guinea-pig cerebral cortex membranes correlate well with the affinity constants obtained for alpha-1B-adrenoceptors in rat spleen membranes. The affinities of selective compounds for the alpha-1B-adrenoceptor subtype in guinea-pig cerebral cortex correlate very well with their affinity for alpha-1B-adrenoceptor in the rat spleen homogenate. Both regression lines coincide with the line of identity. The affinity constants of selective compounds for the alpha-1A-adrenoceptors in guinea-pig cerebral cortex only apparently correlate with the affinity for either the alpha-1B-adrenoceptors in guinea-pig cerebral cortex or in the rat spleen. Regression analyses indicate a straight line relationship (r2>0.9) between PK(alpha-1A) and pK(alpha-1B) but the regression lines deviate from the line of identity.